The potential of topoisomerase I inhibitors in the treatment of CNS malignancies: report of a synergistic effect between topotecan and radiation

Summary Despite innovations in imaging, surgery, and radiation therapy, local failure remains the principle clinical problem in most CNS malignancies. To date, chemotherapy has not made a major impact in the treatment of most adult CNS tumors. The inroads made by chemotherapy in pediatric CNS malignancies suggest that novel drugs, or drug combinations, may improve therapy. Topoisomerase I (Topo I) inhibitors are a relatively new group of chemotherapy drugs with a novel mechanism of action. Drugs in this group currently undergoing clinical trials are the Camptothecin analogues Topotecan, CPT-11, and 9-aminocamptothecin. There is substantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS malignancies. Preclinical studies with the water soluble Topo I inhibitor, Topotecan, demonstrate antineoplastic activity in a variety of CNS malignancies. In addition, Topotecan has good CNS penetration in primates, and recent preliminary phase I and II clinical trials of Topotecan in pediatric and adult CNS malignancies have been promising. In this paper, we describe the unique mechanism of action, antineoplastic activity, and radiosensitizing properties of Topo I inhibitors. We present the first report demonstrating potentiation of radiation lethality by Topotecan in a human glioma (1354) cell line. The dose enhancement ratio was 3.2 at 10% survival. Thus, there is evidence to suggest that Topo I inhibitors may be beneficial in the treatment of CNS neoplasms on the basis of their antineoplastic activity alone, as well as their radiosensitizing effects. Two clinical trials which utilize concurrent Topotecan and radiation in the treatment of pediatric and adult CNS malignancies are discussed.     

Head injury mortality in two centers with different emergency medical services and intensive care

The authors report data collected prospectively on 551 cases of head injury in New Delhi, India, and 822 cases in Charlottesville, Virginia. The mortality rate, adjusted for initial severity of injury, was 11.0% in New Delhi versus 7.2% in Charlottesville (p less than 0.02). There was a striking similarity in mortality rates at both centers when comparing patients with the least severe head injuries and those with the most severe injuries according to the motor score of the Glasgow Coma Scale (GCS M). However, in the group with an abnormal but purposeful motor response (GCS M = 5), the mortality rate was 12.5% in New Delhi versus 4.8% in Charlottesville (p less than 0.01). The relative absence of prehospital emergency care and the delay in admission after head injury in New Delhi are cited as two possible causes for the differences in mortality rates in this subgroup of patients with "moderate" head injuries.     

Atherosclerotic cardiovascular disease risk in the HAART-treated HIV-1 population

Atherosclerotic cardiovascular disease (CVD), a leading cause of morbidity and mortality in the general population, is also an increasing cause for concern for HIV-infected patients. A number of risk factors for CVD are also associated with HIV disease and HIV therapy, particularly insulin resistance, metabolic dyslipidemia, and inflammation. For example, atherogenic dyslipidemia, a side effect of HIV therapy, is an established risk for CVD in the non-HIV-infected population. As our understanding of atherosclerotic disease evolves, new markers of CVD risk have been identified, including metabolic syndrome definitions and C-reactive protein, a marker of inflammation. Use of these markers, in association with established risk factor guidelines, may serve as important tools in helping HIV physicians implement drug regimens that allow optimum management of metabolic complications associated with HIV and HAART, and thereby reduce CVD risk. The objective of this article is to review the mechanisms of atherosclerotic CVD and to discuss risk factors and markers that can be applied in the evaluation and treatment of CVD in the HIV-positive population.     

Does the MMR vaccine and secretin or its receptor share an antigenic epitope?

In a subgroup of children with autism-spectrum like conditions symptoms seem to appear as a 'regression' (in normal development). It has been postulated that the onset of such autistic symptoms may involve an autoimmune response against the central nervous system and that the antigenic determinant could possibly be gastrointestinal in origin. It has been suggested that the presence of the measles virus and 'autistic enterocolitis' demonstrates the possibility that the MMR triple vaccine may be mediating the inflammation with possible production of antibodies against the virus containing vaccine. Such an antibody may share antigenic determinant to molecules found in the gut. We propose that this may be secretin or its receptor, found in the gut as well as in the central nervous system. The antibody response to the gut may also conceivably occur in the brain at a critical time in development. The modulation of development by secretin may be a static event possibly occurring at a specific time in early childhood development and if it involves an autoimmune response then a disruption in development may result. These hypothesized events can only occur if the MMR vaccine shares antigenic determinants that resemble secretin or any of its receptor types and remains to be studied.     

Role of radiation therapy in small cell lung cancer: a bio-clinico-pathological review and perspective

The role of radiotherapy in small cell carcinoma of the lung is unsettled; however, the radiosensitivity of this neoplasm is unquestioned. The ability of radiotherapy to cure or improve patients with this disease is still undergoing study. A review of this challenging subject is presented.     

Immunological studies with different classes of mutants affected at the adenosine kinase locus in CHO cells

Adenosine kinase (AK) from CHO cells has been purified to homogeneity and specific antibodies to it have been raised in rabbits. Using this antibody, the presence of a specific cross-reacting protein (CRP) in cell extracts of different classes of mutants resistant to purine nucleoside analogs which are affected in AK has been investigated by the immunoblotting technique. Results of our studies show that 31 of the 32 independently selected class A AK^– mutants (obtained at high frequency in presence of adenosine analogs toyocamycin, tubercidin, 6-methylmercaptopurine riboside, or pyrazofurin and containing no measurable activity of AK in cell extracts) contained similar amounts of a specific CRP as seen in the parental AK⁺ cells. The CRP in the parental and different mutant cell lines has the same relative molecular mass as purified AK. Similar results were obtained with two mutants each of the class B and C type (selected in presence of C-nucleosides formycin A and formycin B), which are also affected in AK but show novel properties. The presence of equivalent amounts of the CRP in the vast majority of the class A mutants strongly indicates that the high frequency of those mutants in CHO cells is not a result of an epigenetic or deletion type of event, but that such mutants may contain missense types of mutations at a presumed mutational hot spot within the structural gene for adenosine kinase.